# NM_001770.6(CD19):c.705G>T (p.Pro235=)

https://sugi.bio/variant/cd19-p-pro235

## Summary

**CD19 p.Pro235= (c.705G>T)** is classified **Benign** in CD19 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with immunodeficiency, common variable, 3.

**At a glance:** Benign · review: Multiple submitters · rsID rs35979293 · 9 submitters · 1 linked condition · common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CD19 gene that is classified as benign — not considered disease-causing, submitted by 9 submitters, and is linked to immunodeficiency, common variable, 3.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Diagnostic panels | CD19 is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015668/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CD19](https://sugi.bio/atlas/gene/CD19/) |
| Protein change (HGVS p.) | p.Pro235= |
| Coding change (HGVS c.) | c.705G>T |
| MANE Select transcript | [NM_001770](https://www.ncbi.nlm.nih.gov/nuccore/NM_001770) |
| dbSNP | [rs35979293](https://www.ncbi.nlm.nih.gov/snp/rs35979293/) |
| Variant type | single nucleotide variant |
| Location | chr16:28933379-28933379 (GRCh38) |
| ClinVar | [VCV318805](https://www.ncbi.nlm.nih.gov/clinvar/variation/318805/) |

**All HGVS expressions:** `LRG_35:g.6441G>T`, `LRG_35t1:c.705G>T`, `NC_000016.10:g.28933379G>T`, `NC_000016.9:g.28944700G>T`, `NG_007275.1:g.6441G>T`, `NM_001178098.2:c.705G>T`, `NM_001385732.1:c.438G>T`, `NM_001770.6:c.705G>T`, `NR_169755.1:n.1033G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -1.111 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.191**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **35.8%** (nfe) · FAF95 35.7% · FAF99 35.7% · 422,352/1,179,882 in the highest group · 530,212/1,613,826 alleles overall — common (popmax 35.8%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 44% | 2 |
| Amish (not grpmax-eligible) | 42.3% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 40.9% | 2 |
| European (non-Finnish) (grpmax) | 35.8% | 3 |
| Middle Eastern | 33.5% | 3 |
| Remaining individuals (not grpmax-eligible) | 31.4% | 3 |
| Admixed American | 25.9% | 4 |
| East Asian | 21% | 5 |
| South Asian | 13.9% | 7 |
| African / African-American | 10.6% | 9 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CD19** population constraint: LOEUF 0.627, pLI 0.0059088, missense-Z 1.3202; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency, common variable, 3** — Definitive (AR)

## Protein context {#protein}

Residue **235** lies in the ig-like c2-type 2 domain.

AlphaFold model confidence (whole protein): pLDDT 62.99, 24% of residues very-high.

**4 experimental structure(s)** (PDB): [6AL5](https://www.rcsb.org/structure/6AL5), [7JIC](https://www.rcsb.org/structure/7JIC), [7URV](https://www.rcsb.org/structure/7URV), [7URX](https://www.rcsb.org/structure/7URX) — incl. mutant structure 6AL5.

## What this gene does {#gene-function}

*Describes the biological roles of CD19 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** p.Pro235= falls in the ig-like c2-type 2 domain. In Reactome, CD19 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** CD19 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

CD19 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** B cell proliferation involved in immune response, immunoglobulin mediated immune response, antigen receptor-mediated signaling pathway, regulation of B cell receptor signaling pathway, regulation of B cell activation, positive regulation of release of sequestered calcium ion into cytosol.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (9/9 Benign).

**Submission history:** 9 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-11-10 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-14 |
| Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Benign | criteria provided, single submitter | clinical testing | 2024-01-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-09-26 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-21 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[immunodeficiency, common variable, 3](https://sugi.bio/atlas/disease/immunodeficiency-common-variable-3/).

**Reported phenotype names (ClinVar):** Immunodeficiency, common variable, 3, not provided, not specified, none provided, AllHighlyPenetrant, ANTIBODY DEFICIENCY DUE TO CD19 DEFECT.

## Similar variants {#similar}

Related CD19 variant pages (same residue, condition, or type): [CD19 p.Pro235Leu](/variant/cd19-p-pro235leu), [CD19 p.Pro235Ser](/variant/cd19-p-pro235ser), [CD19 c.835+3A>G](/variant/cd19-c-835-plus-3a-g), [CD19 p.Arg163His](/variant/cd19-p-arg163his), [CD19 p.Arg263His](/variant/cd19-p-arg263his), [CD19 p.Arg490Gln](/variant/cd19-p-arg490gln), [CD19 p.Arg76Ser](/variant/cd19-p-arg76ser), [CD19 p.Gln345His](/variant/cd19-p-gln345his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 318805). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*